Generalized Epilepsy with Febrile Seizures Plus

Mendelian MONDO:0018214 Pathograph 11 Show in embeddings browser Epilepsy Channelopathy

Generalized (genetic) epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a marked autosomal dominant hereditary tendency, incomplete penetrance, and striking intrafamilial phenotypic variability. The defining feature is "febrile seizures plus" (FS+): febrile seizures that persist beyond the usual age of ~6 years and/or are accompanied by afebrile generalized tonic-clonic seizures. The phenotypic spectrum ranges from simple febrile seizures and FS+ at the mild end, through afebrile generalized seizures (absence, myoclonic, atonic) and focal seizures, to severe developmental and epileptic encephalopathies such as myoclonic-atonic epilepsy and Dravet syndrome (the severe end of the SCN1A spectrum) at the severe end. GEFS+ is mechanistically a channelopathy/synaptopathy: pathogenic variants in voltage-gated sodium channel genes (SCN1A, SCN1B, SCN9A), GABA-A receptor subunit genes (GABRG2, GABRD), and synaptic-release machinery (STX1B) converge on impaired inhibitory neurotransmission and neuronal network hyperexcitability.

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1
Inheritance
4
Pathophys.
7
Phenotypes
11
Pathograph
6
Genes
5
Medical Actions
6
Subtypes
1
Trials
1
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant with incomplete penetrance HP:0000006
GEFS+ is inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity. Reported pedigree penetrance estimates range from ~60% to ~80%, and a de novo origin becomes more common toward the severe (Dravet) end of the SCN1A spectrum.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (2 references)
PMID:11591834 SUPPORT Human Clinical
"Inheritance was autosomal dominant with a penetrance of about 80%."
Direct quantitative penetrance estimate from a large multigenerational GEFS+ family, supporting autosomal dominant inheritance with incomplete penetrance.
PMID:20301494 SUPPORT Human Clinical
"Each child of an individual with an SCN1A seizure disorder has a 50% chance of inheriting the pathogenic variant; however, the risk of developing seizures is less than 100% because of reduced penetrance."
GeneReviews confirms autosomal dominant inheritance with reduced penetrance across the SCN1A seizure disorder spectrum that includes GEFS+.
◆

Subtypes

6
GEFS+ type 2 (SCN1A, Nav1.1)
SCN1A hgnc:10585 {'name': 'Autosomal dominant'}
The major and most clinically important GEFS+ locus (GEFS2, chromosome 2q24), caused by heterozygous variants in SCN1A (Nav1.1 alpha subunit). GEFS+ SCN1A variants are predominantly missense; truncating/loss-of-function variants are more often associated with the severe Dravet syndrome end of the spectrum.
Show evidence (1 reference)
PMID:11254444 SUPPORT Human Clinical
"A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A."
Establishes SCN1A (GEFS2) as the major GEFS+ subtype locus.
GEFS+ type 1 (SCN1B, Nav beta-1)
SCN1B hgnc:10586 {'name': 'Autosomal dominant'}
The first GEFS+ gene discovered (GEFS1, chromosome 19q13.1), caused by variants in SCN1B encoding the voltage-gated sodium channel beta-1 modulatory subunit. The classic variant is C121W (p.Cys121Trp), which disrupts a conserved extracellular disulfide bridge and impairs beta-1 modulation of channel gating (loss of function).
Show evidence (1 reference)
PMID:9697698 SUPPORT Human Clinical
"We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B)."
Establishes SCN1B (GEFS1, 19q13.1) as the first-described GEFS+ subtype locus.
GEFS+ (GABRG2, GABA-A receptor gamma-2)
GABRG2 hgnc:4087 {'name': 'Autosomal dominant'}
GEFS+ caused by variants in GABRG2 encoding the GABA-A receptor gamma-2 subunit. Variant classes include missense, nonsense, frameshift, point, and splice-site mutations; the gamma-2 subunit has a special role in receptor trafficking, so many variants reduce surface expression and inhibitory synaptic transmission.
Show evidence (1 reference)
PMID:39143639 SUPPORT Human Clinical
"the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene."
Establishes GABRG2 as a major GEFS+ subtype gene.
GEFS+ (STX1B, syntaxin-1B)
STX1B hgnc:18539 {'name': 'Autosomal dominant'}
Fever-associated epilepsy/GEFS+ spectrum caused by variants in STX1B encoding syntaxin-1B, a presynaptic SNARE protein essential for synaptic vesicle exocytosis. Heterozygous loss of function impairs neurotransmitter release and confers temperature-sensitive network instability.
GEFS+ (SCN9A, Nav1.7)
SCN9A hgnc:10597 {'name': 'Autosomal dominant'}
Additional sodium-channelopathy contributor to the GEFS+/febrile seizure spectrum via variants in SCN9A encoding Nav1.7, increasing neuronal excitability.
GEFS+ (GABRD, GABA-A receptor delta)
GABRD hgnc:4084 {'name': 'Autosomal dominant'}
GEFS+ susceptibility associated with variants in GABRD encoding the extrasynaptic GABA-A receptor delta subunit, reducing tonic GABAergic inhibition.
⚙

Pathophysiology

4
Voltage-gated sodium channel dysfunction
Heterozygous variants in the neuronal voltage-gated sodium channel alpha-subunit SCN1A (Nav1.1) and the modulatory beta-1 subunit SCN1B alter channel gating and inactivation. The classic SCN1B C121W variant impairs the beta-1 subunit's ability to modulate channel-gating kinetics in a loss-of-function manner, while SCN1A missense variants (often in conserved domains/S4 voltage sensors) shift gating/inactivation. These channelopathies established the founding "idiopathic epilepsies are channelopathies" paradigm.
GABAergic inhibitory interneuron CL:0000617
Sodium ion transmembrane transport GO:0035725 ⚠ ABNORMAL Membrane depolarization GO:0051899 ↑ INCREASED
Downstream
Impaired GABAergic inhibition Reduced excitability of Nav1.1-dependent GABAergic interneurons lowers inhibitory drive onto excitatory networks.
Network hyperexcitability and seizures Altered sodium-channel gating contributes to seizure susceptibility and fever sensitivity.
Show evidence (2 references)
PMID:9697698 SUPPORT In Vitro
"Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele."
Functional electrophysiology directly demonstrates loss-of-function of the SCN1B C121W variant on sodium-channel gating, the founding mechanism for GEFS+.
PMID:9697698 SUPPORT Human Clinical
"This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns."
Establishes the channelopathy framework underlying GEFS+ and predicts additional sodium-channel subunit involvement (later confirmed for SCN1A).
Impaired GABAergic inhibition
GEFS+ variants in the GABA-A receptor subunit genes GABRG2 (gamma-2) and GABRD (delta) reduce inhibitory GABAergic neurotransmission. GABRG2 variants span missense, nonsense, frameshift, point, and splice-site classes; because the gamma-2 subunit is central to receptor trafficking, many variants reduce surface receptor expression and chloride conductance. In parallel, because Nav1.1 (SCN1A) is preferentially expressed in GABAergic interneurons, loss-of-function SCN1A variants reduce interneuron firing, producing a convergent disinhibition mechanism.
GABAergic inhibitory interneuron CL:0000617
GABAergic synaptic transmission GO:0051932 ↓ DECREASED GABA signaling pathway GO:0007214 ↓ DECREASED Chloride transmembrane transport GO:1902476 ↓ DECREASED
Downstream
Network hyperexcitability and seizures Reduced inhibitory tone shifts the excitation/inhibition balance toward hyperexcitability, producing febrile and afebrile seizures.
Show evidence (2 references)
PMID:39143639 SUPPORT In Vitro
"All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy."
Establishes reduced GABA-A receptor (ion channel) function at the cell membrane as the core mechanism of GABRG2-related GEFS+.
PMID:39143639 SUPPORT In Vitro
"The γ2 subunit plays a special role in receptor trafficking and is closely related to its structural specificity."
Identifies receptor trafficking as a central mechanism by which GABRG2 variants reduce surface GABA-A receptor expression and inhibition.
Synaptic vesicle exocytosis dysfunction
Variants in STX1B (syntaxin-1B), a presynaptic SNARE protein, impair synaptic vesicle exocytosis and neurotransmitter release. Heterozygous Stx1b loss-of-function mouse models recapitulate fever-associated epilepsy, linking presynaptic release machinery to temperature-sensitive network instability in the GEFS+ spectrum.
GABAergic inhibitory interneuron CL:0000617
Synaptic vesicle exocytosis GO:0016079 ↓ DECREASED
Downstream
Network hyperexcitability and seizures Impaired presynaptic vesicle release (predominantly from inhibitory interneurons) destabilizes the excitation/inhibition balance, contributing to temperature-sensitive network hyperexcitability and seizures.
Show evidence (2 references)
PMID:25362483 SUPPORT Human Clinical
"Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy."
Establishes STX1B (syntaxin-1B), a presynaptic SNARE protein, as a GEFS+ spectrum gene linking impaired synaptic vesicle release machinery to fever-associated epilepsy.
PMID:25362483 SUPPORT Model Organism
"Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature."
Zebrafish stx1b knockdown recapitulates temperature-sensitive seizure-like activity, linking presynaptic release dysfunction to fever-triggered network instability in the GEFS+ spectrum.
Network hyperexcitability and seizures
Convergent loss of inhibitory neurotransmission (sodium-channel dysfunction in interneurons, reduced GABA-A receptor function, impaired vesicle release) shifts cortical and hippocampal networks toward hyperexcitability. Fever and elevated temperature act as physiologic triggers, lowering the seizure threshold and producing febrile seizures, FS+, and afebrile generalized or focal seizures.
Excitatory pyramidal neuron CL:0000598
Action potential GO:0001508 ↑ INCREASED
Downstream
Febrile seizures Network hyperexcitability produces fever-triggered seizures in early childhood.
Febrile seizures plus (FS+) GEFS+ network hyperexcitability produces febrile seizures that persist beyond the usual age range or accompany afebrile generalized seizures.
Generalized tonic-clonic seizures Hyperexcitable networks produce afebrile or fever-associated bilateral tonic-clonic seizures.
Absence seizures Additional generalized seizure types can include absence seizures.
Myoclonic seizures Additional generalized seizure types can include myoclonic seizures.
Atonic seizures Additional generalized seizure types can include atonic seizures.
Focal-onset seizures GEFS+ network hyperexcitability can also present with focal-onset seizures.
Show evidence (1 reference)
PMID:9697698 SUPPORT Human Clinical
"We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures."
Defines the GEFS+ clinical phenotype (fever-triggered seizures persisting beyond 6 years and/or afebrile generalized seizures) arising from the network hyperexcitability mechanism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Generalized Epilepsy with Febrile Seizures Plus Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Nervous System 5
Febrile seizures FREQUENT Febrile seizure (within the age range of 3 months to 6 years) HP:0002373
Show evidence (2 references)
PMID:11591834 SUPPORT Human Clinical
"The most common phenotypes are febrile seizures (FS) often with accessory afebrile generalized tonic-clonic seizures (GTCS, FS(+))."
Supports febrile seizures as the most common (FREQUENT) manifestation within GEFS+ families specifically, justifying the frequency band.
PMID:9697698 SUPPORT Human Clinical
"Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder."
Provides the general-population frequency context for febrile seizures, the core manifestation in the GEFS+ spectrum.
Generalized tonic-clonic seizures Bilateral tonic-clonic seizure HP:0002069
Show evidence (1 reference)
PMID:39143639 SUPPORT Human Clinical
"generalized tonic-clonic seizures (GTCSs) with fever commonly occur between 3 months and 6 years of age, which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs."
Documents generalized tonic-clonic seizures as part of the GEFS+ phenotypic spectrum.
Absence seizures FREQUENT Generalized non-motor (absence) seizure HP:0002121
Show evidence (2 references)
PMID:11591834 SUPPORT Human Clinical
"In about one third, additional seizure types occur, such as absences, myoclonic, or atonic seizures."
Supports absence seizures as an additional GEFS+ seizure type, occurring in about one third of affected individuals.
ORPHA:36387 SUPPORT Other
"HP:0002121 | Generalized non-motor (absence) seizure | Frequent (79-30%)"
Orphanet records absence seizures as frequent in GEFS+.
Myoclonic seizures OCCASIONAL Generalized myoclonic seizure HP:0002123
Show evidence (1 reference)
PMID:11591834 SUPPORT Human Clinical
"In about one third, additional seizure types occur, such as absences, myoclonic, or atonic seizures."
Supports myoclonic seizures as an additional GEFS+ seizure type.
Focal-onset seizures Focal-onset seizure HP:0007359
Show evidence (1 reference)
PMID:39143639 SUPPORT Human Clinical
"which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs."
Documents focal seizures within the accepted GEFS+ phenotypic spectrum.
Other 2
Febrile seizures plus (FS+) Complex febrile seizure HP:0011172
Temporal: PROLONGED
Show evidence (1 reference)
PMID:9697698 SUPPORT Human Clinical
"many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures"
Directly describes the FS+ phenotype that defines GEFS+, distinguishing it from simple febrile seizures.
Atonic seizures OCCASIONAL Atonic seizure HP:0010819
Show evidence (1 reference)
PMID:11591834 SUPPORT Human Clinical
"In about one third, additional seizure types occur, such as absences, myoclonic, or atonic seizures."
Supports atonic seizures as an additional GEFS+ seizure type.
🧬

Genetic Associations

6
SCN1A (Major GEFS+ locus (GEFS2, 2q24); predominantly missense variants in familial GEFS+, with truncating/loss-of-function variants associated with the severe Dravet end of the spectrum.)
Gene: SCN1A hgnc:10585 relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (3 references)
PMID:11254444 SUPPORT Human Clinical
"A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A."
Establishes SCN1A as the GEFS2 locus, the major causative gene for GEFS+.
PMID:11254444 SUPPORT Human Clinical
"On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%."
Provides a quantitative mutation-frequency estimate for SCN1A/SCN1B in familial GEFS+ cases.
PMID:11254445 SUPPORT Human Clinical
"This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family."
Independent confirmation of SCN1A as a GEFS+ gene with the novel W1204R variant.
SCN1B (First GEFS+ gene identified (GEFS1, 19q13.1); classic C121W (p.Cys121Trp) loss-of-function variant impairing beta-1 modulation of sodium channels.)
Gene: SCN1B hgnc:10586 relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:9697698 SUPPORT Human Clinical
"We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B)."
Original discovery of SCN1B as the first GEFS+ gene via linkage and mutation identification.
GABRG2 (Major GEFS+ gene encoding the GABA-A receptor gamma-2 subunit; missense, nonsense, frameshift, point, and splice-site variants reduce receptor trafficking and inhibitory function.)
Gene: GABRG2 hgnc:4087 relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:39143639 SUPPORT Human Clinical
"the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene."
Establishes GABRG2 as a major causative gene for GEFS+.
PMID:39143639 SUPPORT Human Clinical
"The predominant types of GABRG2 mutations include missense (c.983A → T, c.245G → A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site (IVS6+2T → G) mutations."
Catalogs the major GABRG2 variant classes reported in GEFS+.
STX1B (Synaptic SNARE gene (syntaxin-1B) implicated in fever-associated epilepsy/GEFS+ spectrum; supported by heterozygous knockout mouse models.)
Gene: STX1B hgnc:18539 relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:39143639 PARTIAL Human Clinical
"GEFS+ exhibits significant genetic heterogeneity"
Supports genetic heterogeneity of GEFS+ extending beyond the core sodium-channel and GABA-A genes to synaptic genes such as STX1B.
SCN9A (Additional sodium-channel (Nav1.7) contributor to the GEFS+/febrile seizure spectrum.)
Gene: SCN9A hgnc:10597 relationship_type: RISK_FACTOR
Autosomal dominant
Show evidence (1 reference)
PMID:39143639 PARTIAL Human Clinical
"GEFS+ exhibits significant genetic heterogeneity"
Supports inclusion of additional implicated sodium-channel genes such as SCN9A within the heterogeneous GEFS+ genetic landscape.
GABRD (GABA-A receptor delta subunit; extrasynaptic tonic-inhibition contributor to GEFS+ susceptibility.)
Gene: GABRD hgnc:4084 relationship_type: RISK_FACTOR
Autosomal dominant
Show evidence (1 reference)
PMID:39143639 PARTIAL Human Clinical
"GEFS+ exhibits significant genetic heterogeneity"
Supports the inclusion of additional GABA-A receptor subunit genes such as GABRD within the heterogeneous GEFS+ genetic landscape.
💊

Medical Actions

5
Anti-seizure medication (broad-spectrum)
Action: pharmacotherapy MAXO:0000058
Agent: valproic acid CHEBI:39867 levetiracetam CHEBI:6437 clobazam CHEBI:31413
Broad-spectrum anti-seizure medications used across the GEFS+/SCN1A spectrum include valproic acid, levetiracetam, topiramate, clobazam, stiripentol, benzodiazepines, cannabidiol, and ethosuximide. There are no uniformly effective antiepileptic drugs for the treatment-refractory minority of GEFS+ families.
Show evidence (2 references)
PMID:20301494 SUPPORT Human Clinical
"stiripentol, benzodiazepines, cannabidiol, topiramate, levetiracetam, valproic acid, and ethosuximide."
GeneReviews lists the anti-seizure medications used across the SCN1A seizure disorder spectrum that includes GEFS+.
PMID:39143639 SUPPORT Human Clinical
"discussing novel aspects deemed to be great significance for clinically accurate diagnosis, anti-epileptic treatment strategies, and new drug development."
Supports that GEFS+ management centers on anti-epileptic treatment strategies and that new drug development remains an active need.
Avoidance of sodium-channel-blocking ASMs (SCN1A spectrum)
Action: avoidance of contraindicated anti-seizure medication Ontology label: pharmacotherapy MAXO:0000058
In SCN1A-related disorders (including the severe end of the GEFS+ spectrum), sodium-channel-blocking anti-seizure medications such as carbamazepine, lamotrigine, vigabatrin, and phenytoin can induce or worsen seizures and should generally be avoided. This is a critical genotype-directed prescribing caveat captured here as a behavioral management action.
Show evidence (1 reference)
PMID:20301494 SUPPORT Human Clinical
"Agents/circumstances to avoid: ASMs: carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis"
GeneReviews drug-safety warning that sodium-channel-blocking ASMs can worsen seizures in SCN1A disorders within the GEFS+ spectrum.
Ketogenic diet
Action: dietary intervention MAXO:0000088
The ketogenic diet has reduced seizure frequency in some affected individuals across the SCN1A seizure disorder spectrum.
Show evidence (1 reference)
PMID:20301494 SUPPORT Human Clinical
"Use of the ketogenic diet to decrease seizure frequency has been beneficial in some affected individuals."
GeneReviews supports the ketogenic diet as a beneficial dietary intervention for seizure control in SCN1A disorders.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling is indicated for families with GEFS+ given autosomal dominant inheritance with reduced penetrance and a 50% transmission risk per child.
Show evidence (1 reference)
PMID:20301494 SUPPORT Human Clinical
"Each child of an individual with an SCN1A seizure disorder has a 50% chance of inheriting the pathogenic variant"
Supports genetic counseling given the autosomal dominant 50% transmission risk in SCN1A seizure disorders including GEFS+.
SCN1A-upregulating gene therapy (ETX101, investigational)
Action: gene therapy MAXO:0001001
ETX101 is an investigational AAV9-delivered engineered transcription factor designed to increase SCN1A expression in inhibitory (GABAergic) neurons, being evaluated for SCN1A-positive Dravet syndrome at the severe end of the SCN1A/GEFS+ spectrum (ENDEAVOR, NCT05419492, Phase 1/2).
Show evidence (1 reference)
clinicaltrials:NCT05419492 SUPPORT Human Clinical
"ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome"
Documents the investigational SCN1A-upregulating gene therapy program for the severe (Dravet) end of the SCN1A/GEFS+ spectrum.
🔬

Clinical Trials

1
NCT05419492 PHASE_II RECRUITING
ENDEAVOR: Phase 1/2 study of ETX101, an AAV9-delivered engineered transcription factor that upregulates SCN1A in GABAergic neurons, in infants and children with SCN1A-positive Dravet syndrome (severe end of the SCN1A/GEFS+ spectrum).
Target Phenotypes: Generalized tonic-clonic seizure HP:0002069
Show evidence (1 reference)
clinicaltrials:NCT05419492 SUPPORT
"ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome"
Trial of a gene therapy targeting the SCN1A loss-of-function mechanism shared with the GEFS+ spectrum.
{ }

Source YAML

click to show 
name: Generalized Epilepsy with Febrile Seizures Plus
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
  Generalized (genetic) epilepsy with febrile seizures plus (GEFS+) is a
  familial epilepsy syndrome with a marked autosomal dominant hereditary
  tendency, incomplete penetrance, and striking intrafamilial phenotypic
  variability. The defining feature is "febrile seizures plus" (FS+): febrile
  seizures that persist beyond the usual age of ~6 years and/or are accompanied
  by afebrile generalized tonic-clonic seizures. The phenotypic spectrum ranges
  from simple febrile seizures and FS+ at the mild end, through afebrile
  generalized seizures (absence, myoclonic, atonic) and focal seizures, to severe
  developmental and epileptic encephalopathies such as myoclonic-atonic epilepsy
  and Dravet syndrome (the severe end of the SCN1A spectrum) at the severe end.
  GEFS+ is mechanistically a channelopathy/synaptopathy: pathogenic variants in
  voltage-gated sodium channel genes (SCN1A, SCN1B, SCN9A), GABA-A receptor
  subunit genes (GABRG2, GABRD), and synaptic-release machinery (STX1B) converge
  on impaired inhibitory neurotransmission and neuronal network hyperexcitability.
disease_term:
  preferred_term: Generalized Epilepsy with Febrile Seizures Plus
  term:
    id: MONDO:0018214
    label: generalized epilepsy with febrile seizures plus
external_assertions:
- name: Orphanet generalized epilepsy with febrile seizures plus record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:36387
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=36387
  description: >-
    Orphanet's ORPHA:36387 structured record for generalized epilepsy with
    febrile seizures plus includes the exact MONDO and OMIM cross-references,
    autosomal dominant inheritance, and HPO seizure annotations used in this
    entry.
  evidence:
  - reference: ORPHA:36387
    reference_title: "Generalized epilepsy with febrile seizures-plus (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0018214 | Exact"
    explanation: Orphanet maps ORPHA:36387 exactly to the MONDO identifier used by this entry.
  - reference: ORPHA:36387
    reference_title: "Generalized epilepsy with febrile seizures-plus (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:604233 | Exact"
    explanation: Orphanet lists OMIM:604233 as an exact external cross-reference for the GEFS+ phenotypic series.
parents:
- Epilepsy
- Channelopathy
synonyms:
- GEFS+
- genetic epilepsy with febrile seizures plus
- epilepsy with febrile seizures plus

references:
- reference: PMID:20301494
  title: "SCN1A Seizure Disorders."
  tags:
  - GeneReviews

inheritance:
- name: Autosomal dominant with incomplete penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    GEFS+ is inherited in an autosomal dominant manner with incomplete
    penetrance and variable expressivity. Reported pedigree penetrance
    estimates range from ~60% to ~80%, and a de novo origin becomes more
    common toward the severe (Dravet) end of the SCN1A spectrum.
  evidence:
  - reference: PMID:11591834
    reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inheritance was autosomal dominant with a penetrance of about 80%."
    explanation: >-
      Direct quantitative penetrance estimate from a large multigenerational
      GEFS+ family, supporting autosomal dominant inheritance with
      incomplete penetrance.
  - reference: PMID:20301494
    reference_title: "SCN1A Seizure Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with an SCN1A seizure disorder has a 50%
      chance of inheriting the pathogenic variant; however, the risk of
      developing seizures is less than 100% because of reduced penetrance.
    explanation: >-
      GeneReviews confirms autosomal dominant inheritance with reduced
      penetrance across the SCN1A seizure disorder spectrum that includes GEFS+.

has_subtypes:
- name: GEFS+2 (SCN1A)
  display_name: GEFS+ type 2 (SCN1A, Nav1.1)
  description: >-
    The major and most clinically important GEFS+ locus (GEFS2, chromosome 2q24),
    caused by heterozygous variants in SCN1A (Nav1.1 alpha subunit). GEFS+ SCN1A
    variants are predominantly missense; truncating/loss-of-function variants are
    more often associated with the severe Dravet syndrome end of the spectrum.
  genes:
  - preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:11254444
    reference_title: "Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second locus on chromosome 2q, GEFS2, was recently identified as the
      sodium-channel alpha1-subunit, SCN1A.
    explanation: >-
      Establishes SCN1A (GEFS2) as the major GEFS+ subtype locus.
- name: GEFS+1 (SCN1B)
  display_name: GEFS+ type 1 (SCN1B, Nav beta-1)
  description: >-
    The first GEFS+ gene discovered (GEFS1, chromosome 19q13.1), caused by
    variants in SCN1B encoding the voltage-gated sodium channel beta-1 modulatory
    subunit. The classic variant is C121W (p.Cys121Trp), which disrupts a
    conserved extracellular disulfide bridge and impairs beta-1 modulation of
    channel gating (loss of function).
  genes:
  - preferred_term: SCN1B
    term:
      id: hgnc:10586
      label: SCN1B
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now report linkage, in another large GEFS+ family, to chromosome
      region 19q13.1 and identification of a mutation in the voltage-gated
      sodium (Na+)-channel beta1 subunit gene (SCN1B).
    explanation: >-
      Establishes SCN1B (GEFS1, 19q13.1) as the first-described GEFS+ subtype locus.
- name: GABRG2
  display_name: GEFS+ (GABRG2, GABA-A receptor gamma-2)
  description: >-
    GEFS+ caused by variants in GABRG2 encoding the GABA-A receptor gamma-2
    subunit. Variant classes include missense, nonsense, frameshift, point, and
    splice-site mutations; the gamma-2 subunit has a special role in receptor
    trafficking, so many variants reduce surface expression and inhibitory
    synaptic transmission.
  genes:
  - preferred_term: GABRG2
    term:
      id: hgnc:4087
      label: GABRG2
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the occurrence of GEFS+ is mainly related to mutations in the
      gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene.
    explanation: >-
      Establishes GABRG2 as a major GEFS+ subtype gene.
- name: STX1B
  display_name: GEFS+ (STX1B, syntaxin-1B)
  description: >-
    Fever-associated epilepsy/GEFS+ spectrum caused by variants in STX1B
    encoding syntaxin-1B, a presynaptic SNARE protein essential for synaptic
    vesicle exocytosis. Heterozygous loss of function impairs neurotransmitter
    release and confers temperature-sensitive network instability.
  genes:
  - preferred_term: STX1B
    term:
      id: hgnc:18539
      label: STX1B
  inheritance:
  - name: Autosomal dominant
- name: SCN9A
  display_name: GEFS+ (SCN9A, Nav1.7)
  description: >-
    Additional sodium-channelopathy contributor to the GEFS+/febrile seizure
    spectrum via variants in SCN9A encoding Nav1.7, increasing neuronal
    excitability.
  genes:
  - preferred_term: SCN9A
    term:
      id: hgnc:10597
      label: SCN9A
  inheritance:
  - name: Autosomal dominant
- name: GABRD
  display_name: GEFS+ (GABRD, GABA-A receptor delta)
  description: >-
    GEFS+ susceptibility associated with variants in GABRD encoding the
    extrasynaptic GABA-A receptor delta subunit, reducing tonic GABAergic
    inhibition.
  genes:
  - preferred_term: GABRD
    term:
      id: hgnc:4084
      label: GABRD
  inheritance:
  - name: Autosomal dominant

pathophysiology:
- name: Voltage-gated sodium channel dysfunction
  description: >-
    Heterozygous variants in the neuronal voltage-gated sodium channel
    alpha-subunit SCN1A (Nav1.1) and the modulatory beta-1 subunit SCN1B alter
    channel gating and inactivation. The classic SCN1B C121W variant impairs the
    beta-1 subunit's ability to modulate channel-gating kinetics in a
    loss-of-function manner, while SCN1A missense variants (often in conserved
    domains/S4 voltage sensors) shift gating/inactivation. These channelopathies
    established the founding "idiopathic epilepsies are channelopathies" paradigm.
  cell_types:
  - preferred_term: GABAergic inhibitory interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: Sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: ABNORMAL
  - preferred_term: Membrane depolarization
    term:
      id: GO:0051899
      label: membrane depolarization
    modifier: INCREASED
  evidence:
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Co-expression of the mutant beta1 subunit with a brain Na+-channel
      alpha subunit in Xenopus laevis oocytes demonstrates that the mutation
      interferes with the ability of the subunit to modulate channel-gating
      kinetics consistent with a loss-of-function allele.
    explanation: >-
      Functional electrophysiology directly demonstrates loss-of-function of
      the SCN1B C121W variant on sodium-channel gating, the founding
      mechanism for GEFS+.
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This observation develops the theme that idiopathic epilepsies are a
      family of channelopathies and raises the possibility of involvement of
      other Na+-channel subunit genes in febrile seizures and generalized
      epilepsies with complex inheritance patterns.
    explanation: >-
      Establishes the channelopathy framework underlying GEFS+ and predicts
      additional sodium-channel subunit involvement (later confirmed for SCN1A).
  downstream:
  - target: Impaired GABAergic inhibition
    description: >-
      Reduced excitability of Nav1.1-dependent GABAergic interneurons lowers
      inhibitory drive onto excitatory networks.
  - target: Network hyperexcitability and seizures
    description: >-
      Altered sodium-channel gating contributes to seizure susceptibility and
      fever sensitivity.

- name: Impaired GABAergic inhibition
  description: >-
    GEFS+ variants in the GABA-A receptor subunit genes GABRG2 (gamma-2) and
    GABRD (delta) reduce inhibitory GABAergic neurotransmission. GABRG2 variants
    span missense, nonsense, frameshift, point, and splice-site classes; because
    the gamma-2 subunit is central to receptor trafficking, many variants reduce
    surface receptor expression and chloride conductance. In parallel, because
    Nav1.1 (SCN1A) is preferentially expressed in GABAergic interneurons,
    loss-of-function SCN1A variants reduce interneuron firing, producing a
    convergent disinhibition mechanism.
  cell_types:
  - preferred_term: GABAergic inhibitory interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: GABAergic synaptic transmission
    term:
      id: GO:0051932
      label: synaptic transmission, GABAergic
    modifier: DECREASED
  - preferred_term: GABA signaling pathway
    term:
      id: GO:0007214
      label: gamma-aminobutyric acid signaling pathway
    modifier: DECREASED
  - preferred_term: Chloride transmembrane transport
    term:
      id: GO:1902476
      label: chloride transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All of these mutations types can reduce the function of ion channels on
      the cell membrane; however, the degree and mechanism underlying these
      dysfunctions are different and could be linked to the main mechanism of
      epilepsy.
    explanation: >-
      Establishes reduced GABA-A receptor (ion channel) function at the cell
      membrane as the core mechanism of GABRG2-related GEFS+.
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The γ2 subunit plays a special role in receptor trafficking and is
      closely related to its structural specificity.
    explanation: >-
      Identifies receptor trafficking as a central mechanism by which GABRG2
      variants reduce surface GABA-A receptor expression and inhibition.
  downstream:
  - target: Network hyperexcitability and seizures
    description: >-
      Reduced inhibitory tone shifts the excitation/inhibition balance toward
      hyperexcitability, producing febrile and afebrile seizures.

- name: Synaptic vesicle exocytosis dysfunction
  description: >-
    Variants in STX1B (syntaxin-1B), a presynaptic SNARE protein, impair
    synaptic vesicle exocytosis and neurotransmitter release. Heterozygous
    Stx1b loss-of-function mouse models recapitulate fever-associated epilepsy,
    linking presynaptic release machinery to temperature-sensitive network
    instability in the GEFS+ spectrum.
  cell_types:
  - preferred_term: GABAergic inhibitory interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: Synaptic vesicle exocytosis
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:25362483
    reference_title: "Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the identification of mutations in STX1B, encoding
      syntaxin-1B, that are associated with both febrile seizures and epilepsy.
    explanation: >-
      Establishes STX1B (syntaxin-1B), a presynaptic SNARE protein, as a GEFS+
      spectrum gene linking impaired synaptic vesicle release machinery to
      fever-associated epilepsy.
  - reference: PMID:25362483
    reference_title: "Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Video and local field potential analyses of zebrafish larvae with
      antisense knockdown of stx1b showed seizure-like behavior and
      epileptiform discharges that were highly sensitive to increased temperature.
    explanation: >-
      Zebrafish stx1b knockdown recapitulates temperature-sensitive
      seizure-like activity, linking presynaptic release dysfunction to
      fever-triggered network instability in the GEFS+ spectrum.
  downstream:
  - target: Network hyperexcitability and seizures
    description: >-
      Impaired presynaptic vesicle release (predominantly from inhibitory
      interneurons) destabilizes the excitation/inhibition balance,
      contributing to temperature-sensitive network hyperexcitability and seizures.

- name: Network hyperexcitability and seizures
  description: >-
    Convergent loss of inhibitory neurotransmission (sodium-channel dysfunction
    in interneurons, reduced GABA-A receptor function, impaired vesicle release)
    shifts cortical and hippocampal networks toward hyperexcitability. Fever and
    elevated temperature act as physiologic triggers, lowering the seizure
    threshold and producing febrile seizures, FS+, and afebrile generalized or
    focal seizures.
  cell_types:
  - preferred_term: Excitatory pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: INCREASED
  evidence:
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recently described a clinical subset, termed generalized epilepsy
      with febrile seizures plus (GEFS+), in which many family members have
      seizures with fever that may persist beyond six years of age or be
      associated with afebrile generalized seizures.
    explanation: >-
      Defines the GEFS+ clinical phenotype (fever-triggered seizures persisting
      beyond 6 years and/or afebrile generalized seizures) arising from the
      network hyperexcitability mechanism.
  downstream:
  - target: Febrile seizures
    description: Network hyperexcitability produces fever-triggered seizures in early childhood.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11591834
      reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common phenotypes are febrile seizures (FS) often with
        accessory afebrile generalized tonic-clonic seizures (GTCS, FS(+)).
      explanation: This GEFS+ family study supports febrile seizures as a core outcome of the network epilepsy phenotype.
  - target: Febrile seizures plus (FS+)
    description: GEFS+ network hyperexcitability produces febrile seizures that persist beyond the usual age range or accompany afebrile generalized seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9697698
      reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        many family members have seizures with fever that may persist beyond six
        years of age or be associated with afebrile generalized seizures
      explanation: The founding GEFS+ family study directly describes the FS+ phenotype.
  - target: Generalized tonic-clonic seizures
    description: Hyperexcitable networks produce afebrile or fever-associated bilateral tonic-clonic seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39143639
      reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        generalized tonic-clonic seizures (GTCSs) with fever commonly occur
        between 3 months and 6 years of age, which is generally followed by
        febrile seizure plus (FS+), with or without absence seizures, focal
        seizures, or GTCSs.
      explanation: Review evidence documents generalized tonic-clonic seizures in the GEFS+ spectrum.
  - target: Absence seizures
    description: Additional generalized seizure types can include absence seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11591834
      reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In about one third, additional seizure types occur, such as absences,
        myoclonic, or atonic seizures.
      explanation: Family data support absence seizures as an additional seizure type downstream of GEFS+ network hyperexcitability.
  - target: Myoclonic seizures
    description: Additional generalized seizure types can include myoclonic seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11591834
      reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In about one third, additional seizure types occur, such as absences,
        myoclonic, or atonic seizures.
      explanation: Family data support myoclonic seizures as an additional seizure type downstream of GEFS+ network hyperexcitability.
  - target: Atonic seizures
    description: Additional generalized seizure types can include atonic seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11591834
      reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In about one third, additional seizure types occur, such as absences,
        myoclonic, or atonic seizures.
      explanation: Family data support atonic seizures as an additional seizure type downstream of GEFS+ network hyperexcitability.
  - target: Focal-onset seizures
    description: GEFS+ network hyperexcitability can also present with focal-onset seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39143639
      reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        which is generally followed by febrile seizure plus (FS+), with or
        without absence seizures, focal seizures, or GTCSs.
      explanation: Review evidence documents focal seizures in the GEFS+ spectrum.

phenotypes:
- name: Febrile seizures
  description: >-
    Typical febrile seizures occurring in early childhood (commonly 3 months to
    6 years). In GEFS+ families these are the mildest, most frequent
    manifestation; febrile seizures affect approximately 3% of all children.
  phenotype_term:
    preferred_term: Febrile seizure
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  frequency: FREQUENT
  evidence:
  - reference: PMID:11591834
    reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common phenotypes are febrile seizures (FS) often with
      accessory afebrile generalized tonic-clonic seizures (GTCS, FS(+)).
    explanation: >-
      Supports febrile seizures as the most common (FREQUENT) manifestation
      within GEFS+ families specifically, justifying the frequency band.
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Febrile seizures affect approximately 3% of all children under six years
      of age and are by far the most common seizure disorder.
    explanation: >-
      Provides the general-population frequency context for febrile seizures,
      the core manifestation in the GEFS+ spectrum.
- name: Febrile seizures plus (FS+)
  description: >-
    The defining feature of GEFS+: febrile seizures that persist beyond the usual
    age of ~6 years and/or are associated with afebrile generalized tonic-clonic
    seizures. Modeled here with the closest available HPO term (complex febrile
    seizure); the preferred term captures the GEFS+-specific "plus" concept.
  phenotype_term:
    preferred_term: Febrile seizures plus (febrile seizures persisting beyond age 6 or with afebrile seizures)
    term:
      id: HP:0011172
      label: Complex febrile seizure
    temporality: PROLONGED
  evidence:
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      many family members have seizures with fever that may persist beyond six
      years of age or be associated with afebrile generalized seizures
    explanation: >-
      Directly describes the FS+ phenotype that defines GEFS+, distinguishing
      it from simple febrile seizures.
- name: Generalized tonic-clonic seizures
  description: >-
    Afebrile generalized (bilateral) tonic-clonic seizures, occurring with or
    after febrile seizures across the GEFS+ spectrum.
  phenotype_term:
    preferred_term: Generalized tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      generalized tonic-clonic seizures (GTCSs) with fever commonly occur
      between 3 months and 6 years of age, which is generally followed by
      febrile seizure plus (FS+), with or without absence seizures, focal
      seizures, or GTCSs.
    explanation: >-
      Documents generalized tonic-clonic seizures as part of the GEFS+
      phenotypic spectrum.
- name: Absence seizures
  description: >-
    Generalized non-motor (absence) seizures occurring in a subset of GEFS+
    individuals as part of the afebrile generalized seizure spectrum.
  phenotype_term:
    preferred_term: Absence seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  frequency: FREQUENT
  evidence:
  - reference: PMID:11591834
    reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In about one third, additional seizure types occur, such as absences,
      myoclonic, or atonic seizures.
    explanation: >-
      Supports absence seizures as an additional GEFS+ seizure type, occurring
      in about one third of affected individuals.
  - reference: ORPHA:36387
    reference_title: "Generalized epilepsy with febrile seizures-plus (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002121 | Generalized non-motor (absence) seizure | Frequent (79-30%)"
    explanation: Orphanet records absence seizures as frequent in GEFS+.
- name: Myoclonic seizures
  description: >-
    Generalized myoclonic seizures occurring in a subset of GEFS+ individuals,
    more prominent toward the severe (myoclonic-atonic epilepsy/Dravet) end of
    the spectrum.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0002123
      label: Generalized myoclonic seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:11591834
    reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In about one third, additional seizure types occur, such as absences,
      myoclonic, or atonic seizures.
    explanation: >-
      Supports myoclonic seizures as an additional GEFS+ seizure type.
- name: Atonic seizures
  description: >-
    Atonic (drop) seizures occurring in a subset of GEFS+ individuals, again
    more prominent at the severe end of the spectrum.
  phenotype_term:
    preferred_term: Atonic seizure
    term:
      id: HP:0010819
      label: Atonic seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:11591834
    reference_title: "Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In about one third, additional seizure types occur, such as absences,
      myoclonic, or atonic seizures.
    explanation: >-
      Supports atonic seizures as an additional GEFS+ seizure type.
- name: Focal-onset seizures
  description: >-
    Focal-onset seizures are now recognized within the GEFS+ spectrum, which is
    why the syndrome has been increasingly renamed away from "generalized."
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which is generally followed by febrile seizure plus (FS+), with or
      without absence seizures, focal seizures, or GTCSs.
    explanation: >-
      Documents focal seizures within the accepted GEFS+ phenotypic spectrum.

genetic:
- name: SCN1A
  gene_term:
    preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  association: >-
    Major GEFS+ locus (GEFS2, 2q24); predominantly missense variants in familial
    GEFS+, with truncating/loss-of-function variants associated with the severe
    Dravet end of the spectrum.
  relationship_type: CAUSATIVE
  subtype: GEFS+2 (SCN1A)
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:11254444
    reference_title: "Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second locus on chromosome 2q, GEFS2, was recently identified as the
      sodium-channel alpha1-subunit, SCN1A.
    explanation: >-
      Establishes SCN1A as the GEFS2 locus, the major causative gene for GEFS+.
  - reference: PMID:11254444
    reference_title: "Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the basis of SSCA, the combined frequency of SCN1A and SCN1B
      mutations in familial cases of GEFS+ was found to be 17%.
    explanation: >-
      Provides a quantitative mutation-frequency estimate for SCN1A/SCN1B in
      familial GEFS+ cases.
  - reference: PMID:11254445
    reference_title: "A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This work has confirmed the role of SCN1A in GEFS+, by identification of
      a novel mutation in a previously undescribed family.
    explanation: >-
      Independent confirmation of SCN1A as a GEFS+ gene with the novel W1204R
      variant.
- name: SCN1B
  gene_term:
    preferred_term: SCN1B
    term:
      id: hgnc:10586
      label: SCN1B
  association: >-
    First GEFS+ gene identified (GEFS1, 19q13.1); classic C121W (p.Cys121Trp)
    loss-of-function variant impairing beta-1 modulation of sodium channels.
  relationship_type: CAUSATIVE
  subtype: GEFS+1 (SCN1B)
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:9697698
    reference_title: "Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now report linkage, in another large GEFS+ family, to chromosome
      region 19q13.1 and identification of a mutation in the voltage-gated
      sodium (Na+)-channel beta1 subunit gene (SCN1B).
    explanation: >-
      Original discovery of SCN1B as the first GEFS+ gene via linkage and
      mutation identification.
- name: GABRG2
  gene_term:
    preferred_term: GABRG2
    term:
      id: hgnc:4087
      label: GABRG2
  association: >-
    Major GEFS+ gene encoding the GABA-A receptor gamma-2 subunit; missense,
    nonsense, frameshift, point, and splice-site variants reduce receptor
    trafficking and inhibitory function.
  relationship_type: CAUSATIVE
  subtype: GABRG2
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the occurrence of GEFS+ is mainly related to mutations in the
      gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene.
    explanation: >-
      Establishes GABRG2 as a major causative gene for GEFS+.
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The predominant types of GABRG2 mutations include missense (c.983A → T,
      c.245G → A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift
      (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site
      (IVS6+2T → G) mutations.
    explanation: >-
      Catalogs the major GABRG2 variant classes reported in GEFS+.
- name: STX1B
  gene_term:
    preferred_term: STX1B
    term:
      id: hgnc:18539
      label: STX1B
  association: >-
    Synaptic SNARE gene (syntaxin-1B) implicated in fever-associated
    epilepsy/GEFS+ spectrum; supported by heterozygous knockout mouse models.
  relationship_type: CAUSATIVE
  subtype: STX1B
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GEFS+ exhibits significant genetic heterogeneity
    explanation: >-
      Supports genetic heterogeneity of GEFS+ extending beyond the core
      sodium-channel and GABA-A genes to synaptic genes such as STX1B.
- name: SCN9A
  gene_term:
    preferred_term: SCN9A
    term:
      id: hgnc:10597
      label: SCN9A
  association: >-
    Additional sodium-channel (Nav1.7) contributor to the GEFS+/febrile seizure
    spectrum.
  relationship_type: RISK_FACTOR
  subtype: SCN9A
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GEFS+ exhibits significant genetic heterogeneity
    explanation: >-
      Supports inclusion of additional implicated sodium-channel genes such as
      SCN9A within the heterogeneous GEFS+ genetic landscape.
- name: GABRD
  gene_term:
    preferred_term: GABRD
    term:
      id: hgnc:4084
      label: GABRD
  association: >-
    GABA-A receptor delta subunit; extrasynaptic tonic-inhibition contributor to
    GEFS+ susceptibility.
  relationship_type: RISK_FACTOR
  subtype: GABRD
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GEFS+ exhibits significant genetic heterogeneity
    explanation: >-
      Supports the inclusion of additional GABA-A receptor subunit genes such
      as GABRD within the heterogeneous GEFS+ genetic landscape.

diagnosis:
- name: Targeted next-generation sequencing (epilepsy gene panel)
  description: >-
    Targeted NGS epilepsy panels are an effective first-step molecular diagnostic
    for GEFS+, which is associated with a limited set of major genes. In a
    monocentric cohort of 1000 pediatric-onset epilepsies, the GEFS+ subgroup had
    a diagnostic yield of 16%; WES/WGS is recommended as a second step.
  evidence:
  - reference: PMID:40347095
    reference_title: "Genetic etiologies with a large NGS panel in a monocentric cohort of 1000 patients with pediatric onset epilepsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with GEFS+ had a yield of 16%."
    explanation: >-
      Provides a real-world diagnostic yield for targeted NGS panel testing in
      GEFS+.
  - reference: PMID:40347095
    reference_title: "Genetic etiologies with a large NGS panel in a monocentric cohort of 1000 patients with pediatric onset epilepsies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome or genome sequencing (WES/WGS) should be considered as a
      second step in these groups with a probably relevant Mendelian
      inheritance.
    explanation: >-
      Supports the tiered diagnostic strategy (panel first, then WES/WGS) for
      Mendelian syndromes including GEFS+.

treatments:
- name: Anti-seizure medication (broad-spectrum)
  description: >-
    Broad-spectrum anti-seizure medications used across the GEFS+/SCN1A spectrum
    include valproic acid, levetiracetam, topiramate, clobazam, stiripentol,
    benzodiazepines, cannabidiol, and ethosuximide. There are no uniformly
    effective antiepileptic drugs for the treatment-refractory minority of GEFS+
    families.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: clobazam
      term:
        id: CHEBI:31413
        label: clobazam
  evidence:
  - reference: PMID:20301494
    reference_title: "SCN1A Seizure Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      stiripentol, benzodiazepines, cannabidiol, topiramate, levetiracetam,
      valproic acid, and ethosuximide.
    explanation: >-
      GeneReviews lists the anti-seizure medications used across the SCN1A
      seizure disorder spectrum that includes GEFS+.
  - reference: PMID:39143639
    reference_title: "GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      discussing novel aspects deemed to be great significance for clinically
      accurate diagnosis, anti-epileptic treatment strategies, and new drug
      development.
    explanation: >-
      Supports that GEFS+ management centers on anti-epileptic treatment
      strategies and that new drug development remains an active need.
- name: Avoidance of sodium-channel-blocking ASMs (SCN1A spectrum)
  description: >-
    In SCN1A-related disorders (including the severe end of the GEFS+ spectrum),
    sodium-channel-blocking anti-seizure medications such as carbamazepine,
    lamotrigine, vigabatrin, and phenytoin can induce or worsen seizures and
    should generally be avoided. This is a critical genotype-directed
    prescribing caveat captured here as a behavioral management action.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of contraindicated anti-seizure medication
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:20301494
    reference_title: "SCN1A Seizure Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: ASMs: carbamazepine, lamotrigine, and
      vigabatrin, which can induce or increase myoclonic seizures; phenytoin,
      which can induce choreoathetosis
    explanation: >-
      GeneReviews drug-safety warning that sodium-channel-blocking ASMs can
      worsen seizures in SCN1A disorders within the GEFS+ spectrum.
- name: Ketogenic diet
  description: >-
    The ketogenic diet has reduced seizure frequency in some affected
    individuals across the SCN1A seizure disorder spectrum.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:20301494
    reference_title: "SCN1A Seizure Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Use of the ketogenic diet to decrease seizure frequency has been
      beneficial in some affected individuals.
    explanation: >-
      GeneReviews supports the ketogenic diet as a beneficial dietary
      intervention for seizure control in SCN1A disorders.
- name: Genetic counseling
  description: >-
    Genetic counseling is indicated for families with GEFS+ given autosomal
    dominant inheritance with reduced penetrance and a 50% transmission risk per
    child.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301494
    reference_title: "SCN1A Seizure Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with an SCN1A seizure disorder has a 50%
      chance of inheriting the pathogenic variant
    explanation: >-
      Supports genetic counseling given the autosomal dominant 50% transmission
      risk in SCN1A seizure disorders including GEFS+.
- name: SCN1A-upregulating gene therapy (ETX101, investigational)
  description: >-
    ETX101 is an investigational AAV9-delivered engineered transcription factor
    designed to increase SCN1A expression in inhibitory (GABAergic) neurons,
    being evaluated for SCN1A-positive Dravet syndrome at the severe end of the
    SCN1A/GEFS+ spectrum (ENDEAVOR, NCT05419492, Phase 1/2).
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  evidence:
  - reference: clinicaltrials:NCT05419492
    reference_title: "ENDEAVOR: A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Infants and Children With SCN1A-Positive Dravet Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety
      and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome
    explanation: >-
      Documents the investigational SCN1A-upregulating gene therapy program for
      the severe (Dravet) end of the SCN1A/GEFS+ spectrum.

clinical_trials:
- name: NCT05419492
  phase: PHASE_II
  status: RECRUITING
  description: >-
    ENDEAVOR: Phase 1/2 study of ETX101, an AAV9-delivered engineered
    transcription factor that upregulates SCN1A in GABAergic neurons, in infants
    and children with SCN1A-positive Dravet syndrome (severe end of the
    SCN1A/GEFS+ spectrum).
  target_phenotypes:
  - preferred_term: Generalized tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: clinicaltrials:NCT05419492
    reference_title: "ENDEAVOR: A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Infants and Children With SCN1A-Positive Dravet Syndrome"
    supports: SUPPORT
    snippet: >-
      ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety
      and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome
    explanation: >-
      Trial of a gene therapy targeting the SCN1A loss-of-function mechanism
      shared with the GEFS+ spectrum.

datasets: []

notes: >-
  GEFS+ sits on a continuum with Dravet syndrome (severe myoclonic epilepsy of
  infancy), which represents the severe end of the SCN1A allelic spectrum;
  truncating/loss-of-function SCN1A variants tend to cause Dravet whereas missense
  variants more often cause GEFS+. Polygenic background appears to modify
  expressivity within GEFS+ families (relatives with more severe phenotypes carry
  higher polygenic risk scores; De Sainte Agathe & Leguern, eBioMedicine 2025,
  PMID:39729883 — commentary without a structured abstract, so used as a note
  rather than a quoted evidence item). Several additional susceptibility genes
  (SLC32A1, HCN1, HCN2, PRRT2) are reported in target-association databases but
  were not retrieved with quotable primary-literature abstracts and are therefore
  omitted from structured genetic entries pending verification.
📚

References & Deep Research

References

1
PMID:20301494
SCN1A Seizure Disorders.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Generalized Epilepsy with Febrile Seizures Plus (GEFS+): Comprehensive Disease Characteristics Report
Edison Scientific Literature 23 citations 2026-06-05T14:14:16.809983

Generalized Epilepsy with Febrile Seizures Plus (GEFS+): Comprehensive Disease Characteristics Report

Target Disease

  • Disease name: Generalized epilepsy with febrile seizures plus (GEFS+)
  • Category: Mendelian (classically autosomal dominant), with evidence for modifier/polygenic contributions
  • MONDO ID: MONDO:0018214 (via Open Targets disease mapping) (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)

1. Disease information

1.1 Concise overview

GEFS+ is a familial epilepsy syndrome characterized by febrile seizures (FS) and “febrile seizures plus” (FS+) with variable occurrence of afebrile seizures (generalized and/or focal), showing incomplete penetrance and variable expressivity across affected relatives. (agathe2025polygenicriskscore pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)

A core operational definition for FS+ used in classic and modern sources is persistence of fever-triggered seizures beyond age 6 years and/or association with afebrile generalized tonic-clonic seizures. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2)

1.2 Key identifiers (available in retrieved evidence)

Disease name Main synonyms MONDO ID Orphanet ID OMIM/MIM IDs mentioned in evidence ICD-10 ICD-11 MeSH Notes
Generalized epilepsy with febrile seizures plus GEFS+; genetic epilepsy with febrile seizures plus; epilepsy with febrile seizures plus MONDO:0018214 Orphanet:36387 GEFS+ [MIM 604236]; GEFS+ type 1 [OMIM 604233]; GEFS+ type 2 [MIM 604236 referenced in retrieved evidence] not retrieved in current evidence not retrieved in current evidence not retrieved in current evidence MONDO and Orphanet IDs supported by Open Targets disease mapping; syndrome name/synonyms supported by recent review and classic papers; OMIM/MIM identifiers reported in classic GEFS+ literature excerpts (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+, escayg2001anovelscn1a pages 8-8, li2024gabrg2mutationsin pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, wallace1998febrileseizuresand pages 1-2)

Table: This table summarizes the key identifiers and commonly used synonyms for generalized epilepsy with febrile seizures plus. It is useful for harmonizing disease terminology across knowledge-base, ontology, and literature sources.

Notes on identifier gaps: ICD-10/ICD-11 and MeSH identifiers were not retrieved in the current evidence corpus; they are therefore not reported here to avoid speculation. (escayg2001anovelscn1a pages 8-8, OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)

1.3 Common synonyms / alternative names

Frequently used synonyms include “genetic epilepsy with febrile seizures plus” and “epilepsy with febrile seizures plus.” (agathe2025polygenicriskscore pages 1-2, li2024gabrg2mutationsin pages 1-2)

1.4 Evidence provenance (individual-level vs aggregated)

  • Aggregated syndrome-level resources and reviews: 2024 disease-focused review of GABRG2 in GEFS+ (Journal of Translational Medicine) provides consolidated definitions, variant classes, and mechanistic hypotheses. (li2024gabrg2mutationsin pages 1-2)
  • Individual/family-level primary genetic studies: large pedigrees and linkage/functional studies (e.g., SCN1B in 1998 and SCN1A in 2001) define inheritance and establish causal variants. (wallace1998febrileseizuresand pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)

2. Etiology

2.1 Disease causal factors (primary)

GEFS+ is primarily a genetic epilepsy syndrome with prominent contributions from ion channel and synaptic genes, particularly voltage-gated sodium channel genes and GABA-A receptor subunit genes. (li2024gabrg2mutationsin pages 1-2, wallace1998febrileseizuresand pages 1-2)

Classic genetic evidence established SCN1B (Nav β1 subunit) as a GEFS+ gene through linkage to 19q13.1 and a co-segregating missense variant with functional loss of β1 modulation. (wallace1998febrileseizuresand pages 1-2)

Subsequently, SCN1A (Nav1.1 α subunit) was established as a major locus (GEFS2/2q) with multiple missense mutations identified in familial cases, and estimates of mutation frequencies in familial cohorts. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)

2.2 Risk factors

Genetic risk factors (causal genes)

Core genes consistently highlighted as causative/major contributors include SCN1A, SCN1B, and GABRG2. (agathe2025polygenicriskscore pages 1-2, li2024gabrg2mutationsin pages 1-2)

Additional genes supported in aggregated disease–target evidence include STX1B, SLC32A1, HCN1/HCN2, SCN9A, PRRT2, and GABRD (evidence anchored to PubMed IDs listed in Open Targets). (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)

Environmental/physiologic triggers

Fever and temperature elevation are key triggers (by definition), and temperature-dependence has been discussed since early family-based work (“possible temperature dependence” noted in classic SCN1B family) and is consistent with later model-system literature emphasizing heat-induced seizures in related channelopathies. (wallace1998febrileseizuresand pages 1-2, gyamfi2025voltagegatedsodiumchannel pages 14-16)

2.3 Protective factors

Protective genetic or environmental factors were not explicitly identified in the retrieved evidence corpus; current evidence emphasizes modifier effects rather than clearly protective alleles. (agathe2025polygenicriskscore pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)

2.4 Gene–environment interactions

Modern commentary explicitly frames GEFS+ as an autosomal dominant disease with incomplete penetrance and variable expressivity, where outcome variability may reflect interactions between a pathogenic variant and other genetic factors (and potentially environmental factors). (agathe2025polygenicriskscore pages 1-2)

A 2025 eBioMedicine commentary on a 2024 GEFS+ family study reports that relatives with more severe phenotypes had higher polygenic risk scores, supporting a model where polygenic background modifies expressivity of rare pathogenic variants. (agathe2025polygenicriskscore pages 1-2)

3. Phenotypes (with HPO suggestions)

Phenotype category Description (with key age ranges) Suggested HPO terms Frequency/statistics if available Evidence source context IDs
Febrile seizures (FS) Typical febrile seizures in otherwise neurologically normal children; usually occur from 6 months to 5 years, and in GEFS+ families may cease by 6 years; one review notes GTCS with fever commonly occur between 3 months and 6 years, with many patients having seizure termination in mid-childhood (average ~11 years). HP:0002373 Febrile seizures; HP:0002069 Generalized tonic-clonic seizure FS occurred in 41% of 201 individuals from 31 GEFS+ families; median onset 12 months; remission reported at 2 years in one study; febrile seizures affect ~3% of all children and 2–4% in another summary; GEFS+ pedigrees show penetrance ~60%, and one family 89% / another report ~80% (li2024gabrg2mutationsin pages 6-7, li2024gabrg2mutationsin pages 1-2, wallace1998febrileseizuresand pages 1-2, meyer2024characterizationsofa pages 9-12, lerche2001generalizedepilepsywith pages 1-2) (li2024gabrg2mutationsin pages 1-2, li2024gabrg2mutationsin pages 6-7, wallace1998febrileseizuresand pages 1-2, meyer2024characterizationsofa pages 9-12, lerche2001generalizedepilepsywith pages 1-2)
Febrile seizures plus (FS+) FS+ differs from typical FS because febrile attacks continue beyond age 6 years and/or include afebrile tonic-clonic seizures; can include: (1) FS lasting >6 years, (2) GTCS beyond FS, or (3) only FS after age 6. HP:0011172 Febrile seizures plus; HP:0002069 Generalized tonic-clonic seizure FS+ occurred in 20% of 201 individuals from 31 GEFS+ families; median onset 14 months; remission reported from 6 to 34 years; GEFS+ severity category 3 in a 2025 commentary defined as FS persisting after 6 years or associated with afebrile generalized seizures (li2024gabrg2mutationsin pages 6-7, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2) (li2024gabrg2mutationsin pages 6-7, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2)
Afebrile generalized seizures GEFS+ includes afebrile seizures in addition to fever-associated seizures; generalized seizure phenotypes reported include tonic-clonic, myoclonic, absence, and atonic seizures, and more severe phenotypes such as myoclonic-astatic epilepsy. HP:0002069 Generalized tonic-clonic seizure; HP:0002123 Myoclonic seizure; HP:0002121 Absence seizure; HP:0002120 Atonic seizure About one-third of affected individuals in one classic family series had additional seizure types beyond FS/FS+; GEFS+ combined SCN1A/SCN1B mutation frequency in familial cases was 17% in one 2001 cohort, illustrating genetic heterogeneity rather than phenotype frequency (lerche2001generalizedepilepsywith pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, wallace1998febrileseizuresand pages 1-2) (lerche2001generalizedepilepsywith pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, wallace1998febrileseizuresand pages 1-2)
Afebrile focal seizures Later nomenclature shifted from “generalized” because many patients experience focal seizures; recent review states FS+ may occur with or without focal seizures. HP:0007359 Focal-onset seizure No robust phenotype frequency retrieved in current evidence; focal seizures are part of the accepted spectrum (li2024gabrg2mutationsin pages 1-2, agathe2025polygenicriskscore pages 1-2) (li2024gabrg2mutationsin pages 1-2, agathe2025polygenicriskscore pages 1-2)
Mixed/complex seizure presentations GEFS+ may present as FS/FS+ with absence, myoclonic, focal, or dystonic seizures; severe end of spectrum can include myoclonic sudden epilepsy, severe myoclonic epilepsy in infants/Dravet syndrome, and myoclonic-atonic epilepsy. HP:0002123 Myoclonic seizure; HP:0002121 Absence seizure; HP:0007359 Focal-onset seizure; HP:0001250 Seizures Phenotypic severity in one 2025 analysis was classified into 5 categories from no seizures to developmental and epileptic encephalopathy; GEFS+ is generally considered benign but includes severe spectrum disorders (li2024gabrg2mutationsin pages 6-7, agathe2025polygenicriskscore pages 1-2) (li2024gabrg2mutationsin pages 6-7, agathe2025polygenicriskscore pages 1-2)
Developmental / behavioral features GEFS+ classically often does not affect development, but mild intellectual impairment can occur in some affected individuals; severe spectrum disorders overlapping with GEFS+ may include developmental and epileptic encephalopathies. HP:0001249 Intellectual disability; HP:0001263 Global developmental delay Most affected subjects in one classic report had normal or superior intellect except one mildly intellectually impaired proband; no GEFS+-wide developmental prevalence estimate retrieved (li2024gabrg2mutationsin pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2) (li2024gabrg2mutationsin pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2)

Table: This table summarizes the supported GEFS+ phenotypic spectrum, onset/remission timing, and available frequencies from classic and recent evidence. It is useful for mapping clinical features to HPO terms and capturing temporal disease characteristics for a knowledge base.

Key spectrum concepts include: - FS and FS+ at the mild end, with variable additional afebrile seizure types (absence, myoclonic, atonic). (lerche2001generalizedepilepsywith pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2) - A spectrum extending to more severe developmental and epileptic encephalopathy (DEE) phenotypes such as Dravet syndrome and myoclonic-atonic epilepsy. (agathe2025polygenicriskscore pages 1-2)

4. Genetic / molecular information

4.1 Causal genes (supported in retrieved evidence)

A gene-centric synthesis of major and additional supported genes is provided below.

Gene (HGNC symbol) Protein/role (ion channel/synaptic) Evidence for association (classic paper/review + context IDs) Example pathogenic variants or mutation classes (as reported) Inheritance notes/penetrance if available Mechanistic theme
SCN1B Voltage-gated sodium channel β1 subunit; channel modulatory subunit First GEFS+ gene discovery in a large family: Wallace et al. 1998; also summarized in Wallace et al. 2001 and later commentary/review (wallace1998febrileseizuresand pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2) C121W / p.Cys121Trp; coding mutation at nt 387 C>G; loss-of-function β1 modulation reported (wallace1998febrileseizuresand pages 2-3, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, agathe2025polygenicriskscore pages 1-2) Major autosomal dominant gene in GEFS+ pedigrees; classic pedigree analysis estimated ~60% penetrance for GEFS+ families, with incomplete penetrance/variable expressivity emphasized in later reviews (wallace1998febrileseizuresand pages 1-2, agathe2025polygenicriskscore pages 1-2) Impaired β1 modulation of Na+ channel gating/inactivation leading to increased sodium influx, membrane depolarization, and neuronal hyperexcitability (wallace1998febrileseizuresand pages 2-3, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)
SCN1A Voltage-gated sodium channel α1 / Nav1.1 pore-forming subunit GEFS2 locus and SCN1A association established in 2000–2001 papers; frequency and phenotype spectrum reviewed in 2001 and 2024 papers (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, escayg2001anovelscn1a pages 1-2, li2024gabrg2mutationsin pages 1-2) T875M, R1648H; D188V, V1353L, I1656M; W1204R; missense variants enriched in GEFS+; truncating variants more often associated with Dravet syndrome (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, escayg2001anovelscn1a pages 1-2, meyer2024characterizationsofa pages 9-12) Familial GEFS+ is typically autosomal dominant with incomplete penetrance and phenotypic heterogeneity; SCN1A mutations accounted for ~5.6% of 53 unrelated GEFS+ index cases and combined SCN1A/SCN1B mutations for ~17% of familial cases in one 2001 series (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2) Altered channel gating/inactivation, especially S4 voltage-sensor effects; reduced inhibitory interneuron excitability is emphasized in modern Nav1.1 literature (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, gyamfi2025voltagegatedsodiumchannel pages 14-16)
GABRG2 GABA-A receptor γ2 subunit; ligand-gated chloride channel subunit Major GEFS+ gene in recent review; listed among main causative genes in 2025 commentary and Open Targets evidence (li2024gabrg2mutationsin pages 1-2, agathe2025polygenicriskscore pages 1-2, OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Missense (c.983A>T, c.245G>A, p.Met199Val), nonsense (R136, Q390, W429), frameshift (c.1329delC, p.Val462fs33, p.Pro59fs*12), point (P83S), splice-site (IVS6+2T>G); p.Arg82Gln highlighted in polygenic modifier study (li2024gabrg2mutationsin pages 1-2, agathe2025polygenicriskscore pages 1-2, li2024gabrg2mutationsin media a0660f7d) Often segregates in large autosomal dominant GEFS+ families; variable expressivity and incomplete/Mendelian complexity discussed, with environmental and modifier effects noted (li2024gabrg2mutationsin pages 1-2, li2024gabrg2mutationsin pages 6-7, agathe2025polygenicriskscore pages 1-2) Reduced GABA-A receptor function via impaired receptor trafficking, altered surface expression, ER stress/endocytosis-related defects, and diminished inhibitory synaptic transmission (li2024gabrg2mutationsin pages 1-2, li2024gabrg2mutationsin pages 6-7, li2024gabrg2mutationsin media a0660f7d)
STX1B Syntaxin-1B; synaptic vesicle exocytosis / presynaptic release machinery Supported in Open Targets/ClinGen-linked evidence and 2024 mouse-model work for fever-associated epilepsy/GEFS+ spectrum (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+, meyer2024characterizationsofa pages 9-12) Specific human variant examples not retrieved in current evidence set; heterozygous knockout/model evidence available (meyer2024characterizationsofa pages 9-12) Familial cases with variable expressivity are reported in the broader literature, but penetrance figures were not retrieved in current evidence Synaptic transmission defect affecting vesicle release and network excitability; fever sensitivity supported by Stx1b model work (meyer2024characterizationsofa pages 9-12)
SLC32A1 Vesicular inhibitory amino acid transporter (VIAAT/VGAT); loads GABA/glycine into synaptic vesicles Supported by Open Targets disease-target evidence and cited literature for GEFS+ association (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Specific variants not detailed in retrieved full-text evidence; association supported by PMID-linked target evidence (PMID 34038384 in Open Targets evidence row) (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Inheritance/penetrance not retrieved in current evidence Impaired vesicular loading of inhibitory neurotransmitters, reducing inhibitory synaptic transmission (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)
HCN1 Hyperpolarization-activated cyclic nucleotide-gated channel 1; pacemaker cation channel Supported by Open Targets disease-target evidence and cited literature for GEFS+ (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Specific variants not described in retrieved excerpts; literature support includes PMID-linked evidence (e.g., 30351409 in Open Targets) (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Inheritance/penetrance not retrieved in current evidence Altered Ih/pacemaker conductance and neuronal excitability (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)
HCN2 Hyperpolarization-activated cyclic nucleotide-gated channel 2; pacemaker cation channel Supported by Open Targets disease-target evidence and cited literature for GEFS+ (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Specific variants not described in retrieved excerpts; literature support includes PMID-linked evidence in Open Targets row (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Inheritance/penetrance not retrieved in current evidence Altered Ih-mediated rhythmicity/excitability contributing to seizure susceptibility (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)
SCN9A Voltage-gated sodium channel α subunit Nav1.7 Supported by Open Targets disease-target evidence; also listed among additional implicated genes in commentary/review (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+, agathe2025polygenicriskscore pages 1-2) Specific GEFS+-causal variants not detailed in retrieved excerpts (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Inheritance/penetrance not retrieved in current evidence Sodium channel dysfunction increasing neuronal excitability; exact GEFS+-specific mechanism not detailed in retrieved excerpts (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+, agathe2025polygenicriskscore pages 1-2)
PRRT2 Proline-rich transmembrane protein 2; synaptic/exocytosis-associated protein Supported by Open Targets disease-target evidence for GEFS+ (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Specific variants not detailed in retrieved excerpts; literature support includes PMIDs 25522171 and 28007585 in Open Targets evidence (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Inheritance/penetrance not retrieved in current evidence Likely synaptic release/exocytosis dysfunction affecting neuronal network stability (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)
GABRD GABA-A receptor δ subunit; extrasynaptic inhibitory receptor subunit Supported by Open Targets disease-target evidence for Orphanet GEFS+ and cited literature (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Specific variants not detailed in retrieved excerpts; literature support includes PMIDs 15115768, 29785705, 34633442 in Open Targets evidence (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+) Inheritance/penetrance not retrieved in current evidence Reduced tonic GABAergic inhibition via δ-subunit dysfunction, promoting hyperexcitability (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+)

Table: This table summarizes the principal genes currently supported in the retrieved evidence for GEFS+ and the main mechanistic themes linking them to disease. It combines classic discovery papers with recent reviews and target-association evidence to show how sodium-channel, GABAergic, and synaptic genes converge on neuronal hyperexcitability.

4.2 Pathogenic variant classes and examples

  • SCN1B: C121W / p.Cys121Trp is the classic co-segregating familial GEFS+ variant, absent in controls and shown to impair β1 function in a Xenopus oocyte co-expression system. (wallace1998febrileseizuresand pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)
  • SCN1A: multiple missense variants, including variants in conserved S4 segments (e.g., T875M, R1648H) and additional familial variants (D188V, V1353L, I1656M) with reported frequency estimates in familial cohorts. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)
  • GABRG2: the 2024 review summarizes missense, nonsense, frameshift, point, and splice-site variants, with example nomenclature including p.Met199Val, R136*, Q390*, W429*, p.Val462fs*33, and IVS6+2T>G. (li2024gabrg2mutationsin pages 1-2)

Visual evidence (variant catalog)

Cropped regions of Li et al. (2024) Table 2 summarize GABRG2 variant types and associated phenotypes/mechanisms. (li2024gabrg2mutationsin media a0660f7d, li2024gabrg2mutationsin media 969b1bdb, li2024gabrg2mutationsin media 78a53eaa, li2024gabrg2mutationsin media 591accf4)

4.3 Modifier genes / polygenic background

A 2025 eBioMedicine commentary summarizes evidence that polygenic risk score (PRS) can stratify severity among relatives carrying pathogenic variants in GEFS+ families, consistent with polygenic modification of a primarily Mendelian syndrome. (agathe2025polygenicriskscore pages 1-2)

4.4 Epigenetic information / chromosomal abnormalities

No GEFS+-specific epigenetic signatures or recurrent chromosomal abnormalities were retrieved in the current evidence corpus. (li2024gabrg2mutationsin pages 1-2)

5. Environmental information

Beyond fever/temperature as a key physiologic trigger, additional environmental contributors (toxins, lifestyle) were not systematically addressed in the retrieved GEFS+-focused sources. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, li2024gabrg2mutationsin pages 1-2)

6. Mechanism / pathophysiology

6.1 Causal chain (genotype → cellular dysfunction → network hyperexcitability → seizures)

SCN1B: A β1-subunit loss-of-function variant disrupts modulation of sodium-channel gating/inactivation, which is hypothesized to increase sodium influx, depolarize membranes, and promote hyperexcitability. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, wallace1998febrileseizuresand pages 1-2)

SCN1A: Missense variants in conserved channel domains (including S4 voltage-sensor segments) are proposed to alter gating/inactivation, contributing to seizure susceptibility and fever sensitivity in the GEFS+/SCN1A spectrum. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)

GABRG2: GEFS+ variants reduce GABA-A receptor function at the cell membrane and implicate receptor trafficking as a central mechanism (“γ2 subunit plays a special role in receptor trafficking”). (li2024gabrg2mutationsin pages 1-2)

6.2 Immune / inflammatory contributions (emerging, preclinical)

A recent therapeutics-oriented review highlights inflammatory mediators (e.g., IL-6, TNFα) as associated with seizure recurrence and describes suppression of seizures in model systems by blocking the STAT3–IL-6 pathway or using anti-IL-6 monoclonal antibody approaches, supporting immune-modulatory hypotheses relevant to fever-triggered epilepsies. (gyamfi2025voltagegatedsodiumchannel pages 14-16)

6.3 Ontology suggestions

GO biological process (suggestions): - regulation of membrane depolarization / action potential firing - synaptic transmission, GABAergic - ion transmembrane transport - regulation of synaptic vesicle exocytosis

Cell Ontology (CL) cell types (suggestions): - GABAergic interneuron - glutamatergic pyramidal neuron - microglial cell (given inflammatory pathway discussions)

(These are ontology suggestions consistent with mechanisms described in the cited evidence; they are not asserted as direct annotations unless formally demonstrated in the cited studies.) (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2, li2024gabrg2mutationsin pages 1-2, gyamfi2025voltagegatedsodiumchannel pages 14-16)

7. Anatomical structures affected

Primary involvement is the central nervous system, particularly neuronal networks mediating excitation/inhibition balance.

UBERON suggestions: - UBERON:0000955 brain - UBERON:0001017 central nervous system

Relevant cellular compartments include ion-channel/receptor localization at the plasma membrane and receptor trafficking pathways. (li2024gabrg2mutationsin pages 1-2, wallace2001neuronalsodiumchannelalpha1subunit pages 1-2)

8. Temporal development

Typical temporal features include: - Onset: fever-associated generalized tonic–clonic seizures commonly reported from 3 months to 6 years in a recent review, and febrile seizures are classically concentrated in early childhood. (li2024gabrg2mutationsin pages 1-2, wallace1998febrileseizuresand pages 1-2) - Course: many cases remit in childhood (one early family average seizure termination ~11 years), but FS+ may persist longer (remission reported up to adulthood in cohort summaries). (li2024gabrg2mutationsin pages 1-2, li2024gabrg2mutationsin pages 6-7)

9. Inheritance and population

9.1 Inheritance

GEFS+ is classically autosomal dominant with incomplete penetrance and variable expressivity. (agathe2025polygenicriskscore pages 1-2, li2024gabrg2mutationsin pages 1-2)

Quantitative penetrance estimates reported in classic studies include ~60% penetrance in some pedigrees and ~80% penetrance in one family-based report. (wallace1998febrileseizuresand pages 1-2, lerche2001generalizedepilepsywith pages 1-2)

9.2 Epidemiology

Robust GEFS+-specific prevalence/incidence estimates were not retrieved in the current evidence corpus.

However, febrile seizures in the general pediatric population are common, reported as approximately 3% of children in a classic genetics paper and 2–4% in another summary source. (wallace1998febrileseizuresand pages 1-2, meyer2024characterizationsofa pages 9-12)

10. Diagnostics

10.1 Clinical evaluation

Clinical work-up commonly includes: - Seizure semiology and history (including fever association, persistence beyond age 6) - EEG and neuroimaging (CT/MRI) as part of syndrome characterization (no GEFS+-specific performance metrics were retrieved). (meyer2024characterizationsofa pages 9-12)

10.2 Genetic testing

A practical diagnostic pathway supported by a large clinical cohort: - Targeted next-generation sequencing (TNGS) epilepsy panels as a first step in syndromes with major genes (explicitly including GEFS+), with a reported 16% yield in GEFS+ (62 patients) in a 1000-patient pediatric epilepsy cohort. (barcia2025geneticetiologieswith pages 2-4) - WES/WGS as second-tier testing when panel testing is negative in likely Mendelian syndromes; broader pediatric epilepsy practice shows WGS/WES can deliver substantial yield (example: 37.9% molecular diagnosis rate in a 733-family cohort, not GEFS+-specific). (barcia2025geneticetiologieswith pages 1-2)

11. Outcomes / prognosis

GEFS+ is often described as relatively benign in many families but spans a spectrum that includes severe epilepsies (DEE/Dravet/myoclonic-atonic epilepsy). (agathe2025polygenicriskscore pages 1-2)

Natural history data retrieved include: - seizure cessation in mid-childhood in one classic family (average ~11 years), but FS+ remission can extend into adulthood in cohort summaries (6–34 years). (li2024gabrg2mutationsin pages 1-2, li2024gabrg2mutationsin pages 6-7)

SUDEP risk: SUDEP-specific statistics were not retrieved in the current evidence corpus and are not reported here. (agathe2025polygenicriskscore pages 1-2)

12. Treatment

12.1 Current clinical management (anti-seizure medications; supportive care)

GEFS+ treatment largely follows general epilepsy standards (anti-seizure medications, rescue plans, and avoidance/management of fever triggers), but a recent GEFS+ review notes that “there are no particularly effective antiepileptic drugs for the minority of GEFS+ families,” reflecting heterogeneity and treatment-refractory subsets. (li2024gabrg2mutationsin pages 6-7)

12.2 Precision medicine and real-world implementation

A precision-diagnostics study of pediatric epilepsy demonstrates that molecular diagnoses can drive gene-directed therapy decisions (11/55 children), including children with SCN1A variants, illustrating real-world clinical implementation of genotype-informed care even when GEFS+ itself is not uniformly treated with a single gene-specific therapy. (andjelkovic2024characterizationof13 pages 1-2)

12.3 Advanced therapeutics (latest research; 2023–2024 priority)

A major 2024–initiated gene therapy clinical program for the SCN1A spectrum: - ETX101 (Encoded Therapeutics) Phase 1/2 trial NCT05419492 (Recruiting; start 2024-05-14) uses an rAAV9-delivered engineered transcription factor intended to increase SCN1A transcription in inhibitory neurons; primary efficacy endpoint is percent change in monthly countable seizure frequency from baseline to Weeks 5–52; estimated enrollment 47 with age-stratified cohorts. (NCT05419492 chunk 1)

12.4 Structured intervention summary (with MAXO suggestions)

Intervention (drug/device/gene therapy) Indication within GEFS+ spectrum Mechanism/rationale Evidence type Key quantitative details (enrollment, endpoints, yields) MAXO term suggestions Source (context IDs)
ETX101 (rAAV9-delivered gene therapy; one-time ICV administration) SCN1A-positive Dravet syndrome within the SCN1A/GEFS+ spectrum; ClinicalTrials.gov indexing includes “Generalized Epilepsy With Febrile Seizures Plus, Type 2” Engineered transcription factor (eTFSCN1A) under a GABAergic regulatory element (reGABA) designed to increase SCN1A transcription in inhibitory neurons Interventional clinical trial, Phase 1/2 NCT05419492; recruiting; estimated enrollment 47; age cohorts include ≥6 to <36 months, ≥48 months to <18 years, and ≥6 to <48 months; primary efficacy endpoint is percent change in monthly countable seizure frequency from pre-dose baseline to Weeks 5–52; safety endpoints include DLTs, AEs/SAEs, Grade ≥3 AEs, hospitalizations, and overall survival; start date 2024-05-14; primary completion estimated 2028-01 (NCT05419492 chunk 1, NCT05419492 chunk 2) MAXO:gene therapy; MAXO:intracerebroventricular administration; MAXO:seizure monitoring (NCT05419492 chunk 1, NCT05419492 chunk 2)
ETX101 (Australia-only study) SCN1A-positive Dravet syndrome within the broader GEFS+/SCN1A spectrum Same SCN1A upregulation strategy as above; regional safety/efficacy implementation Interventional clinical trial, Phase 1/2 NCT06112275; ACTIVE_NOT_RECRUITING; enrollment 4 participants reported in trial search output; Australian study arm/site implementation (clinical-trial retrieval output) MAXO:gene therapy; MAXO:intracerebroventricular administration (NCT05419492 chunk 1)
Targeted next-generation sequencing (TNGS) epilepsy panel GEFS+ as a Mendelian pediatric epilepsy syndrome with a limited set of recurrent major genes First-step molecular diagnosis to identify pathogenic/likely pathogenic variants in major epilepsy genes and support syndrome-specific management Observational cohort / diagnostic implementation study In a monocentric cohort of 1000 pediatric-onset epilepsies, overall panel yield was 31%; GEFS+ subgroup (n=62) had 16% diagnostic yield; authors conclude TNGS is an effective first-step screen for syndromes associated with one or a few major genes and explicitly include GEFS+ (barcia2025geneticetiologieswith pages 2-4, barcia2025geneticetiologieswith pages 1-2) MAXO:genetic testing; MAXO:targeted gene panel sequencing; MAXO:molecular diagnosis (barcia2025geneticetiologieswith pages 2-4, barcia2025geneticetiologieswith pages 1-2)
Whole-exome sequencing / whole-genome sequencing (WES/WGS) GEFS+ or unresolved SCN1A-spectrum epilepsies after negative panel testing; broader pediatric epilepsy diagnostics Second-tier or first-tier genomic testing to improve diagnosis when targeted panels are negative or phenotype is genetically heterogeneous Observational cohort / diagnostic strategy study Barcia et al. recommend WES/WGS as a second step for groups with likely Mendelian inheritance including GEFS+ after panel testing; in a separate pediatric epilepsy cohort of 733 families, WGS/WES achieved a molecular diagnosis in 278/733 (37.9%), demonstrating utility of genome-scale testing in clinical epilepsy practice (barcia2025geneticetiologieswith pages 2-4) MAXO:whole exome sequencing; MAXO:whole genome sequencing; MAXO:molecular diagnosis (barcia2025geneticetiologieswith pages 2-4)
Gene-directed therapy decisions after NGS SCN1A-related epilepsy phenotypes overlapping GEFS+/Dravet spectrum Molecular diagnosis can alter treatment choices and counseling even when intervention is not syndrome-exclusive Observational precision-medicine study In a 55-child epilepsy cohort analyzed by clinical-exome/WES, diagnostic yield was 50.9% (28/55); 46.4% of diagnosed cases had novel variants; gene-directed therapy decisions were made for 11 children, including 4 carrying novel SCN1A variants (andjelkovic2024characterizationof13 pages 1-2) MAXO:precision medicine intervention; MAXO:genetic testing; MAXO:treatment planning (andjelkovic2024characterizationof13 pages 1-2)
Cannabidiol add-on therapy Severe pediatric epilepsies at the severe end of the GEFS+ spectrum (especially Dravet syndrome rather than typical uncomplicated GEFS+) Broad antiseizure and neuromodulatory effects; cited in GEFS+-focused translational review as part of current therapeutic landscape Review summarizing randomized and real-world clinical evidence Recent GEFS+/GABRG2 review cites randomized and real-world data for cannabidiol in severe pediatric epilepsy, but no GEFS+-specific quantitative efficacy estimate was retrieved in current evidence (li2024gabrg2mutationsin pages 20-21) MAXO:cannabidiol therapy; MAXO:antiseizure medication administration (li2024gabrg2mutationsin pages 20-21)
SAHA/vorinostat (HDAC inhibitor) Experimental GABRG2-related GEFS+ / inhibitory synaptic dysfunction Corrects inhibitory synaptic deficits associated with γ2 missense mutation effects in preclinical systems; mechanistically targets receptor trafficking/synaptic dysfunction Preclinical / translational review GEFS+/GABRG2 review reports that SAHA corrected inhibitory synaptic deficits from γ2 missense mutations in vitro/experimental models; no human trial data retrieved for GEFS+ (li2024gabrg2mutationsin pages 20-21) MAXO:histone deacetylase inhibitor therapy; MAXO:experimental therapy (li2024gabrg2mutationsin pages 20-21)
Dimethyl fumarate repurposing Experimental disease-modification concept for genetic epilepsy/GEFS+ mechanisms Repurposing strategy proposed for pathway modulation in genetic epilepsies Preclinical/translational review Mentioned as a repurposing approach in the 2024 GABRG2/GEFS+ review; no GEFS+-specific clinical efficacy metrics retrieved (li2024gabrg2mutationsin pages 20-21) MAXO:drug repurposing; MAXO:experimental therapy (li2024gabrg2mutationsin pages 20-21)
Hyperthermia seizure-model screening with TRPV4 or NMDA antagonists Experimental fever-triggered SCN1A/GEFS+ mechanisms Preclinical screening platform for heat-induced seizures relevant to GEFS+; targets fever-provoked excitability Preclinical zebrafish/mouse-model review Hyperthermia-induced zebrafish seizure model is rapid, reversible, and non-lethal; TRPV4 antagonists and NMDA receptor antagonists prevented seizures in the model, while GABA reuptake inhibitors did not; supports mechanism-based drug discovery rather than current standard care (gyamfi2025voltagegatedsodiumchannel pages 14-16) MAXO:preclinical drug screening; MAXO:temperature-trigger avoidance not applicable; MAXO:experimental therapy (gyamfi2025voltagegatedsodiumchannel pages 14-16)
Anti-IL-6 / STAT3–IL-6 pathway inhibition Experimental inflammatory modulation for GEFS+-like febrile seizure susceptibility Seizures activate glia and inflammatory pathways; IL-6 pathway blockade suppressed seizures in model systems Preclinical review Intranasal IL-6 increased seizure severity in GEFS+ mice, whereas STAT3-IL-6 pathway inhibition (Stattic) or anti-IL-6 monoclonal antibody significantly suppressed seizures; no human GEFS+ trial data retrieved (gyamfi2025voltagegatedsodiumchannel pages 14-16) MAXO:anti-inflammatory therapy; MAXO:monoclonal antibody therapy; MAXO:experimental therapy (gyamfi2025voltagegatedsodiumchannel pages 14-16)

Table: This table summarizes current clinical and translational applications relevant to GEFS+ and the SCN1A-related epilepsy spectrum, including diagnostic strategies, emerging gene therapy trials, and preclinical mechanism-based treatments. It is useful for linking interventions to evidence type, quantitative details, and MAXO-style action annotations.

13. Prevention

No GEFS+-specific primary prevention strategy was retrieved beyond general epilepsy/febrile seizure best practices (fever management, seizure action plans) and genetic counseling for autosomal dominant familial risk with incomplete penetrance. (agathe2025polygenicriskscore pages 1-2, wallace1998febrileseizuresand pages 1-2)

14. Other species / natural disease

Naturally occurring GEFS+-analog diseases in non-human species were not retrieved in the current evidence corpus. (gyamfi2025voltagegatedsodiumchannel pages 14-16)

15. Model organisms

Evidence in the retrieved corpus supports several model systems relevant to GEFS+ mechanisms: - Xenopus oocyte co-expression electrophysiology used to show impaired SCN1B β1-subunit function for the classic GEFS+ variant. (wallace1998febrileseizuresand pages 1-2) - Mouse models referenced in the context of fever-associated epilepsy and synaptic/threshold changes after complex febrile seizures; and STX1B-related fever-associated epilepsy models. (meyer2024characterizationsofa pages 9-12) - Zebrafish hyperthermia-induced seizure models highlighted as rapid screening tools for fever-triggered seizure mechanisms, with mechanistic intervention testing (e.g., TRPV4 and NMDA antagonists). (gyamfi2025voltagegatedsodiumchannel pages 14-16)

Expert opinion / analysis (evidence-based)

  1. Syndrome definition has evolved: renaming away from “generalized” reflects recognition of focal seizures within the GEFS+ spectrum; this impacts clinical classification and gene-panel design. (li2024gabrg2mutationsin pages 1-2)
  2. GEFS+ is best conceptualized as a spectrum rather than a single phenotype, spanning from FS/FS+ to DEE (e.g., Dravet), and is influenced by both rare variants and background genetic risk. (agathe2025polygenicriskscore pages 1-2)
  3. Clinical implementation trend (2023–2024): expanding use of gene panels followed by WES/WGS in pediatric epilepsy and active development of gene-specific therapies in the SCN1A spectrum signal a near-term shift toward precision medicine in fever-triggered genetic epilepsies. (barcia2025geneticetiologieswith pages 2-4, NCT05419492 chunk 1)

Statistics and recent data points (explicitly retrieved)

  • TNGS panel diagnostic yield in GEFS+: 16% (62 patients) in a 1000-patient pediatric epilepsy cohort. (barcia2025geneticetiologieswith pages 2-4)
  • Cohort phenotype frequencies: FS 41% and FS+ 20% in a 201-person/31-family GEFS+ cohort summary. (li2024gabrg2mutationsin pages 6-7)
  • Penetrance estimates: ~60% penetrance in GEFS+ pedigrees (with higher penetrance in some families; ~80% cited in a classic family analysis). (wallace1998febrileseizuresand pages 1-2, lerche2001generalizedepilepsywith pages 1-2)
  • General pediatric febrile seizure frequency: ~3% in one classic genetics paper; 2–4% in another summary. (wallace1998febrileseizuresand pages 1-2, meyer2024characterizationsofa pages 9-12)

Direct abstract quotes (as required; from retrieved abstracts)

  • Li et al., 2024 (Journal of Translational Medicine; Aug 2024; URL https://doi.org/10.1186/s12967-024-05387-1): “Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait.” (li2024gabrg2mutationsin pages 1-2)
  • Barcia et al., 2025 (Epilepsia Open; May 2025; URL https://doi.org/10.1002/epi4.70057): “Patients with GEFS+ had a yield of 16%.” (barcia2025geneticetiologieswith pages 2-4)

Limitations of this report (evidence availability)

  • PMID coverage: Several classic and review sources were retrieved with DOIs and full text but without explicit PMIDs in the extracted text segments; PubMed IDs are available for some gene–disease links via Open Targets, but a comprehensive PMID-mapped bibliography was not fully recoverable from the current corpus. (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+, wallace1998febrileseizuresand pages 1-2, li2024gabrg2mutationsin pages 1-2)
  • ICD-10/ICD-11/MeSH identifiers were not retrieved and are therefore not reported. (escayg2001anovelscn1a pages 8-8)
  • GEFS+-specific prevalence/incidence and SUDEP risk were not retrieved; only febrile-seizure general-population frequencies and familial penetrance/natural history statistics were available. (meyer2024characterizationsofa pages 9-12, wallace1998febrileseizuresand pages 1-2)

References

  1. (OpenTargets Search: Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+): Open Targets Query (Genetic epilepsy with febrile seizures plus,Generalized epilepsy with febrile seizures plus,GEFS+, 32 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (agathe2025polygenicriskscore pages 1-2): Jean-Madeleine De Sainte Agathe and Eric Leguern. Polygenic risk score to the rescue of monogenic diseases? the case of epilepsy. Jan 2025. URL: https://doi.org/10.1016/j.ebiom.2024.105505, doi:10.1016/j.ebiom.2024.105505. This article has 0 citations and is from a peer-reviewed journal.

  3. (wallace2001neuronalsodiumchannelalpha1subunit pages 1-2): R. Wallace, R. Wallace, I. Scheffer, Scott A. Barnett, M. C. Richards, L. Dibbens, L. Dibbens, R. Desai, T. Lerman-Sagie, D. Lev, A. Mazarib, N. Brand, B. Ben-Zeev, I. Goikhman, Rita Singh, G. Kremmidiotis, G. Kremmidiotis, A. Gardner, G. Sutherland, G. Sutherland, A. George, J. Mulley, J. Mulley, and S. Berkovic. Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. American journal of human genetics, 68 4:859-65, Apr 2001. URL: https://doi.org/10.1086/319516, doi:10.1086/319516. This article has 519 citations and is from a highest quality peer-reviewed journal.

  4. (escayg2001anovelscn1a pages 8-8): Andrew Escayg, Armin Heils, Bryan T. MacDonald, Karsten Haug, Thomas Sander, and Miriam H. Meisler. A novel scn1a mutation associated with generalized epilepsy with febrile seizures plus–and prevalence of variants in patients with epilepsy. American journal of human genetics, 68 4:866-73, Apr 2001. URL: https://doi.org/10.1086/319524, doi:10.1086/319524. This article has 411 citations and is from a highest quality peer-reviewed journal.

  5. (li2024gabrg2mutationsin pages 1-2): Xinxiao Li, Shengnan Guo, Yangyang Sun, Jiangwei Ding, Chao Chen, Yue-hui Wu, Peidong Li, Tao Sun, and Xinjun Wang. Gabrg2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics. Journal of Translational Medicine, Aug 2024. URL: https://doi.org/10.1186/s12967-024-05387-1, doi:10.1186/s12967-024-05387-1. This article has 11 citations and is from a peer-reviewed journal.

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  9. (meyer2024characterizationsofa pages 9-12): Anjela Catherine Meyer. Characterizations of a heterozygous stx1b-knockout mouse model with fever associated epilepsy. Mar 2024. URL: https://doi.org/10.15496/publikation-92758, doi:10.15496/publikation-92758. This article has 0 citations.

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  13. (li2024gabrg2mutationsin media a0660f7d): Xinxiao Li, Shengnan Guo, Yangyang Sun, Jiangwei Ding, Chao Chen, Yue-hui Wu, Peidong Li, Tao Sun, and Xinjun Wang. Gabrg2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics. Journal of Translational Medicine, Aug 2024. URL: https://doi.org/10.1186/s12967-024-05387-1, doi:10.1186/s12967-024-05387-1. This article has 11 citations and is from a peer-reviewed journal.

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  17. (barcia2025geneticetiologieswith pages 2-4): Giulia Barcia, Nicole Chemaly, Stéphanie Gobin‐Limballe, Emma Losito, Mélodie Aubart, Eugénie Sarda, Zahra Assouline, Pauline Plante‐Bordeneuve, Marie Hully, Remi Barrois, Christine Barnerias, Doxa Sareidaki, Delphine Coste Zeitoun, Monika Eisermann, Cécile Fourrage, Sylvain Hanein, Marlène Rio, Nathalie Boddaert, Isabelle Desguerre, Anna Kaminska, Julie Steffann, and Rima Nabbout. Genetic etiologies with a large ngs panel in a monocentric cohort of 1000 patients with pediatric onset epilepsies. Epilepsia Open, 10:1065-1073, May 2025. URL: https://doi.org/10.1002/epi4.70057, doi:10.1002/epi4.70057. This article has 9 citations and is from a peer-reviewed journal.

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